Although the vast majority of cancers arise within readily accessible epithelial surfaces, therapy of epithelial cancers and their precursors remains woefully inadequate for many organ systems. The primary challenges for treating these lesions are 1) oftentimes they are not visible by eye, 2) they may be spatially heterogeneous and distributed over a large surface area, and 3) collateral damage to adjacent, non-involved tissues may cause significant complications. The overall objective of the proposed research is to develop a greatly improved therapeutic technique, 'conformal laser therapy,'for the treatment of epithelial cancers and their precursors. An important component of our approach is comprehensive diagnostic screening, which provides a detailed map of the disease distribution over large mucosal surface areas. Using this map, therapy can be directed to regions known to harbor disease. Unlike prior laser therapies, however, our method has the ability to conform the treatment region (in three-dimensions) to the diseased tissue volume, while minimizing collateral damage. This innovative approach integrates screening with real-time methods for controlling the laser treatment volume based on feedback signals obtained by monitoring local laser- tissue interactions. Conformal laser therapy will leverage 3-dimensional microstructural imaging technology and diagnostic criteria that we have established for comprehensive wide-field screening of epithelial disease. The objective of the R21 is to develop and test methods for monitoring and control. Novel high-resolution, cross-sectional imaging techniques will be investigated for dynamic monitoring of the microscopic consequences of thermal excitation and protein denaturation. In order to control treatment volume, we will exploit the wavelength- dependence of water absorption in the near-infrared (1350-1450 nm), using a tunable laser to vary the depth of thermal injury. Results from the R21 research will guide the construction of a clinically viable system and endoscopic probe for conformal laser therapy during the R33-phase. This instrument will be tested in living swine and the accuracy of this approach for selectively treating epithelial tissues will be determined. Although we focus our research on improving treatment of Barrett's esophagus, this technology will also serve as a platform for wide-field epithelial therapy in a variety of other organ systems where comprehensive treatment and minimal collateral damage are critical.